Environmental Health Perspectives • volume 117 | number 9 | September 2009 1351

Review

There is growing interest within environmental health in disentangling effects of clustered social and environmental exposures and 

exploring potential synergies among these

exposures (Gee and Payne-Sturges 2004; 

Morello-Frosch and Shenassa 2006; O’Neill 

et al. 2003, 2007a, 2007b; Weiss and Bellinger 

2006). This interest stems from the observation 

that social stressors (i.e., violence, poverty) and 

environmental exposures (i.e., traffic-related 

and industrial air pollution) are often spatially 

correlated and may cluster in lower-income 

communities, often in locations with lower 

property values along highways and industrial 

corridors (Bullard 1990; Graves 1988). Trafficrelated air pollution is a complex chemical mix 

(Schauer et al. 2006), often spatially associated with noise, poverty, and other stressors 

(Wheeler and Ben-Shlomo 2005). Social stressors may lead to poor health outcomes directly 

or may increase susceptibility to physical exposures, such as air pollution, through alterations 

in immune function and biological systems 

(McEwen and Seeman 1999). Thus, the most 

pollution-exposed communities may also be 

more susceptible because of higher prevalence 

of social stressors (Lipfert 2004). This potential for spatial confounding and effect modification by social stressors presents a challenge 

to air pollution epidemiology. Disentangling 

social and physical environmental risks (U.S. 

Environmental Protection Agency 2008), 

understanding synergies among these exposures, and identifying modifiable exposures are 

particularly important for understanding how 

best to protect susceptible populations and 

improve overall population health.

There is significant evidence linking trafficrelated pollution exposure to respiratory illness. Chronic exposure to traffic-related and 

particulate air pollution among adults has been 

linked to upper respiratory tract inflammation 

(Hiltermann et al. 1997), chronic obstructive 

pulmonary disease (COPD) (Schikowski et al. 

2005), lung cancer (Vineis et al. 2007), and 

premature mortality (Dockery 1993; Pope et al. 

1995). In children, traffic-related pollution 

exposures, often indicated by residential proximity to major roads, has been associated with 

airway hyperresponsiveness (Jang et al. 2003), 

wheeze (Ryan et al. 2007), asthma (McConnell 

et al. 2006), reduced lung function (Pekkanen 

et al. 1997), and asthma-related hospitalizations 

(Lin et al. 2002; Moore et al. 2008). There is 

now increased interest in understanding cardiovascular effects (Peters 2005; Rückerl et al. 

2006), identifying causal constituents (Lanki 

et al. 2006), and characterizing susceptible subpopulations (O’Neill et al. 2007b).

Psychological stress results when external demands exceed an individual’s perceived 

abilities and resources to meet those demands 

(Cohen et al. 1995) and has been linked to 

respiratory disease and other illness. Limited 

but growing epidemiologic evidence indicates that psychological stress may also alter 

susceptibility to physical exposures, such as 

air pollution. This work examined social–

environmental interactions in respiratory and 

cardiovascular disease, such as stress-related 

modification of traffic-related air pollution 

effects on asthma etiology (Clougherty et al. 

2007) or exacerbation (Chen et al. 2008). 

There is also evidence of stress-related modification in the relationship between bone 

lead level and hypertension among older men 

(Peters et al. 2007). In the same data set, we 

recently identified modification by stress in 

the relation between bone lead and heart 

rate variability (Clougherty JE, Peters JL, 

Schwartz J, Kubzansky L, unpublished data). 

One possible pathway for these differential 

susceptibilities is allostatic load (McEwen and 

Seeman 1999). Allostasis (literally, “achieving stability through change”) refers to the 

body’s ability to adapt to transient stressors 

and exposures. Over time, chronic psychological stress and maladaptive behaviors (e.g., 

poor diet, sleep deprivation) (McEwen 2006) 

may impair the body’s ability to maintain 

allostasis, producing wear and tear on bodily 

systems, compromised immune function, and 

enhanced general susceptibility (McEwen 

2006; McEwen and Seeman 1999), and 

enhancing responsivity to environmental toxicants including air pollution. For example, 

some toxicologic evidence suggests permanent alteration in hypothalamic–pituitary–

adrenal (HPA) function associated with 

chronic stress and lead exposures (Virgolini 

et al. 2005, 2006). However, some biological 

systems involved in maintaining allostasis may 

also be worn down by repeated exposure to 

physical toxicants, as particle exposures may 

influence HPA function (Sirivelu et al. 2006). 

Finally, some air pollutants and psychosocial stress may independently affect common physiologic processes such as oxidative 

Address correspondence to J.E. Clougherty, Harvard 

School of Public Health, Landmark Building, 4th 

Floor West, Boston, MA 02215 USA. Telephone: 

(617) 816-7717. Fax: (617) 384-8859. E-mail: 

jcloughe@hsph.harvard.edu

We are very grateful to B. McEwen for his helpful 

suggestions on this manuscript.

The authors declare they have no competing 

financial interests.

Received 23 January 2009; accepted 12 May 2009.

A Framework for Examining Social Stress and Susceptibility to Air Pollution 

in Respiratory Health

Jane E. Clougherty1 and Laura D. Kubzansky 2

1Department of Environmental Health, and 2Department of Society, Human Development, and Health, Harvard School of Public Health, 

Boston, Massachusetts, USA

Objective: There is growing interest in disentangling the health effects of spatially clustered social 

and physical environmental exposures and in exploring potential synergies among them, with 

particular attention directed to the combined effects of psychosocial stress and air pollution. Both 

exposures may be elevated in lower-income urban communities, and it has been hypothesized that 

stress, which can influence immune function and susceptibility, may potentiate the effects of air pollution in respiratory disease onset and exacerbation. In this paper, we attempt to synthesize the relevant research from social and environmental epidemiology, toxicology, immunology, and exposure 

assessment to provide a useful framework for environmental health researchers aiming to investigate 

the health effects of environmental pollution in combination with social or psychological factors.

Data synthesis: We review the existing epidemiologic and toxicologic evidence on synergistic 

effects of stress and pollution, and then describe the physiologic effects of stress and key issues 

related to measuring and evaluating stress as it relates to physical environmental exposures and susceptibility. Finally, we identify some of the major methodologic challenges ahead as we work toward 

disentangling the health effects of clustered social and physical exposures and accurately describing 

the interplay among these exposures.

Conclusions: There is still tremendous work to be done toward understanding the combined 

and potentially synergistic health effects of stress and pollution. As this research proceeds, we 

recommend careful attention to the relative temporalities of stress and pollution exposures, to nonlinearities in their independent and combined effects, to physiologic pathways not elucidated by 

epidemiologic methods, and to the relative spatial distributions of social and physical exposures at 

multiple geographic scales.

Key words: air pollution, social stress, spatial analysis, synergistic effects, urban community health.

Environ Health Perspect 117:1351–1358 (2009). doi:10.1289/ehp.0900612 available via http://

dx.doi.org/ [Online 12 May 2009]
Clougherty and Kubzansky

1352 volume 117 | number 9 | September 2009 • Environmental Health Perspectives

stress (Fugisawa 2005) or inflammatory cell 

[immunoglobulin E (IgE)] production (DiazSanchez et al. 2000; Nel 2001).

More studies have explored air pollution 

effect modification by socioeconomic status 

(SES) than by stress. Given other evidence of 

greater stress-related illness and susceptibility 

among persons with lower SES (Kubzansky 

et al. 2000; Miller and Chen 2007; Seeman 

et al. 2004), heightened air pollution responses 

with lower SES may be mediated through 

stress-related pathways. The American Cancer 

Society (ACS) studies reported stronger effects 

of air pollution on respiratory, cardiovascular, and all-cause mortality among lower-SES 

persons (Krewski et al. 2000), supported by 

other studies reporting stronger air pollution–

health associations among less-educated adults 

(Finkelstein et al. 2003; Hoek et al. 2002; 

Pope 2002). Time-series studies have indicated that lower-SES persons display stronger 

associations between short-term air pollution 

exposures and health (Jerrett et al. 2004; Lin 

et al. 2004; Martins et al. 2004), although not 

consistently (Zanobetti 2000). These studies, however, have not explored specific components of SES that may be responsible for 

susceptibility effects, although stress has been 

proposed as a key component.

Several theoretical perspectives suggest 

that social, economic, and psychological disadvantage may cluster (Adler and Matthews 

1994; Evans and English 2002; Link and 

Phelan 2000; Shonkoff and Phillips 2000).

Fundamental causes theory, for example, 

describes social conditions (e.g., socioeconomic 

position) as determinants of resource access 

and psychological and behavioral experience, 

shaping disease risk (Link and Phelan 1995). 

Although applicable to combined social and 

physical exposures, these theories have not 

addressed methodologic issues (e.g., spatial correlation, confounding, measurement bias) or 

interpretation challenges arising in combining 

theory, methods, and data across disciplines. 

Like air pollution, low SES and stressors (e.g., 

noise) may be elevated in urban settings along 

highways and industrial areas, and methods are 

needed to disentangle effects of clustered social 

and physical stressors and to investigate potential synergies. One model (Morello-Frosch and 

Shenassa 2006) captures our key constructs 

of interest: a) varied stressors at the individual 

and community level contribute to individual 

chronic stress; b) chronic individual stress is 

embodied as allostatic load, or physiologic wear 

and tear, influencing individual susceptibility; 

and c) stress-borne physiologic susceptibility 

may shape response to environmental exposures, including internal dose, resiliency, likelihood of developing a given illness, and ability 

to recover from it.

Like other models combining social and 

physical exposures (deFur et al. 2007; Gee 

and Payne-Sturges 2004; O’Neill et al. 2003), 

the Morello-Frosch model acknowledges 

that some community-level stressors are also 

physical hazards (e.g., poor housing quality), 

complicating distinctions between effects of 

psychosocial and physical factors. This model 

frames our discussion, although it is outside 

the scope of our review to describe the myriad 

possible social, political, and economic forces 

that contribute to individual stress. Instead, 

we focus our attention on individual-level 

stress and pollution susceptibility, given that 

higher-level stressors need be individually 

embodied to modify pollution effects through 

stress-specific pathways.

We build on conceptual models of social–

environmental interaction by describing key 

methodologic and conceptual issues that 

arise when merging data and methods from 

across environmental and social science traditions. We hope to foster more integrative 

approaches toward understanding combined 

health effects of social and physical environmental exposures. We attempt to synthesize 

the literature to date on the following:

•	Effects of stress on respiratory health and

susceptibility

•	Epidemiologic and toxicologic evidence of

synergistic effects of stress and pollution

•	Pathways through which stress may influence pollution susceptibility

•	Methodologic challenges in merging data

and methods from environmental and 

social sciences.

We aim to provide a template for researchers aiming to rigorously consider combined 

effects on health across disciplines. We hope to 

support the growing literature targeted at disentangling effects of spatially clustered social 

and environmental exposures and exploring 

potential synergies among these exposures.

Physiologic Effects 

of Psychological Stress 

on Respiratory Health 

and Susceptibility

A long history of research links psychological 

stress and respiratory health. In Treatise on 

Asthma, Maimonides (1135–1204) described 

the illness—“Whereas treatment of asthma is 

important, treatment of a patient as a whole 

is more important. For asthma the physician must be a doctor in every sense”—and 

described the importance of clean air and 

its interplay with emotions and hormones 

(Muntner 1963). In the 1930s, Hans Selye 

recognized links between chronic stress in 

laboratory rats and nonspecific susceptibility 

to respiratory distress and death (Selye 1936). 

More recently, chronic stress has been linked 

to asthma symptoms in cross-sectional studies 

(Oh et al. 2004), and prospective studies link 

caregiver stress to infant wheeze (Wright et al. 

2002). Among asthmatic adolescents, SES has 

been associated with stress-linked immune 

mediators [interleukin (IL)-5, interferon-γ], 

an association mediated by stress and control beliefs (Chen et al. 2003). Acute stressors 

(e.g., violent events) may trigger asthma episodes (Sandberg et al. 2000, 2004), and older 

individuals with greater psychological distress 

and anger display faster lung function decline 

over time (Kubzansky et al. 2002).

Distinctions between acute (short-term, 

generally lasting days to weeks) and chronic 

(longer-term, lasting weeks to years) stress is 

not always clear. Some severe acute stressors 

(e.g., sexual violence, or combat) can produce chronic stress effects (i.e., post-traumatic 

stress disorder). Assessing stress chronicity 

is important, however, as acute and chronic 

stress can produce substantively different 

physiologic sequelae, and the predominance 

of acute versus chronic stress experience in a 

given period may shape observed relationships 

between stress and susceptibility. Acute stress 

is linked to sympathetic innervation, including increased ventilation and bronchodilation, 

plausibly masking some short-term effects 

air pollution effects (e.g., acute irritation, 

bronchoconstriction). Conversely, chronic 

stress can produce wear and tear on bodily systems, weaken immune function, and increase 

pollution susceptibility. Because of these very 

different physiologic sequelae, careful consideration of stress chronicity and of the relative 

chronicities of stress and pollution exposures is 

critical in accurately characterizing their interplay and in interpreting interactions.

Acute stress, sympathetic regulation, and 

the fight-or-flight response. Sympathetic nervous system activation under acute stress 

produces the immediate, short-term fightor-flight response. Neural synapses produce 

catecholamines (e.g., epinephrine and norepinephrine or adrenaline and noradrenaline), 

and catabolic functioning breaks down 

metabolites for physical activity and energy 

expenditure. Glucocorticoids are produced, 

including cortisol, increasing heart rate, 

ventilation, myocardial contraction force, 

arterial vasodilation to working muscles, vasoconstriction to nonworking muscles, and dilating pupils and bronchi. Under acute stress, 

parasympathetic nervous system–regulated 

activities subside (e.g., salivary and intestinal 

secretions for digestion and nutrient absorption, growth and repair). Frequent sympathetic nervous system dominance under 

repeated acute stress may interfere with growth 

and repair, especially important for children’s 

development, and suggests one pathway 

through which childhood stress may shape 

lifelong health and susceptibility.

Chronic stress, immune function, and 

inflammatory response. Chronic stress may 

be characterized by recurrent acute stress or 

an inability to moderate acute stress responses 
Stress and air pollution susceptibility

Environmental Health Perspectives • volume 117 | number 9 | September 2009 1353

(McEwen and Seeman 1999). Building on 

Hans Selye’s model of nonspecific susceptibility and allostatic load models of cumulative wear and tear, attention is increasingly 

being directed toward identifying biological 

mediators linking chronic stress to immune 

and endocrine function (Miller et al. 2002; 

Segerstrom and Miller 2004).

Chronic stress and associated negative 

emotional states (e.g., depression, anxiety, 

anger) may mediate immune and endocrine 

processes (Kiecolt-Glaser et al. 2002), with 

associations so consistent that some researchers have proposed reconceptualizing depression as dysfunction in HPA-axis regulation 

and stress response (Sternberg et al. 1992). 

Endocrine responses to chronic stress include 

dysregulation in production of catecholamines 

(epinephrine, norepinephrine), adrenocorticotropin, cortisol, growth hormone, and 

prolactin. Cytokines, particularly IL-6, 

stimulate corticotrophin-releasing hormone 

and HPA-axis activity, increasing plasma 

adrenocorticotropin hormone and cortisol 

(Hellhammer et al. 1997; Kirschbaum et al. 

1995; Ockenfels et al. 1995; Seeman et al. 

1997). Frequent activation of the glucocorti glucocorticoid receptor by cortisol can lead to blunted 

glucocorticoid response (Miller et al. 2002), 

increased nuclear factor-κB signaling (Miller 

et al. 2008), and dysregulated catecholamine 

production (Glaser and Kiecolt-Glaser 2005).

Immune-linked inflammatory response 

may infleunce asthma and related airway 

disease. Asthma-linked parameters responsive 

to stress include IgE (Wright et al. 2004) 

and cytokine production (Chen et al. 2003) 

and respiratory inflammation (Umetsu et al. 

2002). Early life chronic stress may alter 

T-helper (Th)1–Th2 immune cell balance 

(Umetsu et al. 2002), which is linked with 

childhood asthma, allergy, and inflammatory 

responses (Miller and Chen 2007).

Impacts on common physiologic systems.

Growing evidence suggests complex dosedependent interactions among multiple pollutants (Mauderly and Samet 2009), mediated 

through the same mechanistic pathway, or 

some pollutants may potentiate effects of 

others. Similarly, stress may potentiate pollution health effects through immune and 

inflammatory processes, or stress and pollution 

may affect common physiologic systems. Both 

early childhood environmental exposures and 

stress-related catecholamines affect Th1–Th2 

balance (Umetsu et al. 2002). Psychological 

stress (Epel et al. 2004), polycyclic aromatic 

hydrocarbons, cigarette smoke (Adcock and 

Ito 2005), and ozone (Fugisawa 2005) affect 

oxidative stress, which is linked to asthma and 

COPD (Rahman and MacNee 2000). Both 

stress and diesel exhaust particles are associated 

with elevated cytokines (e.g., IL-2, IL-6, and 

local IgE in nasal mucosa) (Diaz-Sanchez et al. 

2000; Nel 2001). Some evidence suggests that 

stress may alter permeability of bodily membranes to chemical exposures, such that stress 

may alter systemic transport and chemical 

uptake into organs including the brain (Sinton 

et al. 2000), facilitating combined and synergistic effects of stressors and pollution on 

many bodily systems.

Key Issues to be Addressed

as This Work Progresses

Careful attention to stress measurement. For 

environmental researchers, social epidemiologic theory and methods for stress measurement may be unfamiliar, but accurately 

understanding and applying these principles 

is necessary to produce meaningful analyses 

of interactions among stressors and pollution 

exposures. Careful attention to stress processes 

and distinction among the major components 

is needed to accurately capture and interpret 

stress effects on susceptibility. Moreover, 

because perceived stress is highly variable over 

time, it is important that measured stress periods are temporally appropriate to the pollution exposures and outcomes under study. 

The stress process is often described in three 

phases: a) the stressor (i.e., any event, condition, or external stimuli posing a physical or 

psychological challenge), b) stress appraisal 

(i.e., how one experiences, perceives, or interprets the event), and c) stress response (e.g., 

psychological and physiologic sequelae).

These phases are interdependent. A stressor appraised as benign or beneficial, rather 

than threatening, generally produces no stress 

response. Highly thorough stress assessments 

would measure each stage, which is rarely feasible. Most studies focus on a single, chronic 

stressor (e.g., caregiver burden) or one unlikely 

to be positively appraised (e.g., exposure to 

violence, natural disaster). Newer measures 

emphasize later stages of the stress process. 

Because of inconsistent findings with stressor 

measures (e.g., life event scales assessing major 

life changes) (Dohrenwend et al. 1993), more 

researchers today use perceived stress measures, 

which capture response to multiple stressors 

(Cohen et al. 1983, 1995). Recent evidence 

indicates, however, that subjective stress may 

poorly predict immune change (Segerstrom 

and Miller 2004); thus, another approach 

emphasizes negative affect (e.g., anxiety, 

depression) as a cumulative indicator of mental distress and psychosocial stress. Negative 

affect may serve as a common final pathway 

for multiple psychological stressors, possibly 

providing a more stable indicator of cumulative stress and susceptibility (Kubzansky et al. 

2000; Seeman et al. 2002).

Other approaches include using biomarkers—hormones or immune markers 

associated with physiological stress responses, 

including glucocorticoids or cytokines (Miller 

et al. 2002). Although many physiologic systems are influenced by acute and chronic stress, 

there is relatively little consensus on optimal 

biomarkers to capture physiologic changes 

with acute or chronic stress. Formerly, corticosteroids (e.g., cortisol) in blood or saliva were 

emphasized as markers of HPA-axis activity, 

although stress-related HPA function changes 

lead to cortisol dysregulation (via glucorticoid 

resistance and HPA regulation), not simply 

increased cortisol production. Thus, cortisol 

can be difficult to interpret and better indicates acute rather than chronic stress. Recent 

research emphasizes indicators of glucocorticoid resistance and neuroendocrine signaling 

(Miller et al. 2008). Other evidence suggests 

that C-reactive protein (Miller G, personal 

communication) and tumor necrosis factor-α

(Clougherty JE, Rossi CA, Lawrence J, 

Long M, Diaz E, Koutrakis P, et al., unpublished data) may capture chronic stress in rats. 

Although no single biomarker is appropriate 

for all applications (Brunner 2007), suites of 

physiologic parameters have been developed 

to represent allostatic load in humans, including indicators of cardiovascular function, 

metabolism, cholesterol, glucose metabolism, 

HPA-axis function, and sympathetic nervous 

system activity (Kubzansky et al. 2000; Seeman 

and Singer 2002). Several studies document 

chronic stress effects on cardiovascular risk 

indicators (abdominal obesity, elevated serum 

triglycerides, low high-density lipoprotein cholesterol, glucose intolerance, elevated blood 

pressure) (Brunner et al. 1997), known collectively as metabolic syndrome, and may provide 

a method for capturing cumulative stress effects 

on cardiovascular and systemic function.

Relative temporality in stress and pollution exposures. Generally, stressors must precede or be contemporaneous with pollution 

exposures to plausibly modify their effects. The 

actual periods of stress and pollution exposures, their overlap, and temporal relation to 

health outcomes, deserve careful attention, 

because temporal exposure misclassification 

may nullify or even reverse the directionality 

of observed interactions. For example, if stress 

exposure occurs after or very late in a pollution exposure interval, interpreting observed 

interactions is problematic. If perceived stress 

is stable over time, the report will accurately 

reflect stress during the hypothesized period 

of susceptibility. If perceived stress varies over 

the period, however, and respondents compare current stress to prior experiences, then 

individuals reporting high stress likely experienced relatively lower stress previously, during 

the pollution exposure period. Such temporal 

misclassification may significantly confound 

results, and researchers should ensure that stress 

and pollution measurement periods support a 

plausible physiologic interaction in relation to 

the health outcome of interest.
Clougherty and Kubzansky

1354 volume 117 | number 9 | September 2009 • Environmental Health Perspectives

Spatial correlations among social and 

physical exposures. Both social and physical 

exposures vary across communities, and lowerincome and minority communities may be 

disproportionately exposed to both (Evans and 

English 2002; Lupien et al. 2001; MorelloFrosch and Shenassa 2006). Strong spatial 

covariance among stress, SES, and pollution 

has confounded geographic information systems (GIS)–based air pollution epidemiology, 

and spatial epidemiologists are challenged to 

differentiate health effects of traffic-related pollution from those of spatially correlated noise, 

stress, or poverty. Evidence suggests that roadway noise, a spatial stressor correlated with 

pollution, increases heart rate among adults 

and children (Belojevic et al. 2008; Belojevic 

and Saric-Tanaskovic 2002), and living in 

high-traffic areas predicts higher stress, lower 

self-reported health, and depressive symptoms 

(Gee and Takeuchi 2004), effects distinct from 

those of pollution per se.

Because of spatial autocorrelation and possible confounding, accurate fine-scale exposure assessment for both stress and pollution 

is critical. GIS-based exposure models, now 

common in environmental epidemiology, 

should be validated to the spatial extent of the 

cohort examined, and spatial patterns in stressors and pollution, at multiple levels, should 

be carefully considered to avoid spatial misclassification and confounding. Social–physical 

correlations may vary by region or context, 

and the appropriate geographic scale of analysis may vary as well. The 1995–1997 Health 

Survey for England found that in urban areas, 

lower-SES households experienced worse air 

quality, although the opposite was true in rural 

regions. Air quality and SES independently 

predicted lung function in both settings, with 

greater pollution susceptibility among lowerSES men, but not women (Wheeler and BenShlomo 2005).

Although some neighborhoods may experience higher average levels of pollution and 

stressors (variation across neighborhoods), one 

should not assume that individuals or residences within these neighborhoods are relatively more exposed to both (variation within 

neighborhoods). Individuals living closer to 

highways likely have higher pollution exposures than do other community residents but 

are not necessarily more exposed to violence 

or family stress. Similarly, U.S. census tracts, 

selected to be relatively homogeneous for key 

sociodemographic indicators, may be a meaningful unit of analysis for some social and economic factors (Subramanian et al. 2005). All 

persons within a census tract, however, do not 

have similar traffic-related pollution exposures, 

which vary dramatically within 50–200 m of 

major roadways (Zhu et al. 2002).

Nonlinear, threshold, and saturation 

effects. There is evidence linking stress and 

air pollution, separately, to asthma onset and 

exacerbation. Because both exposures independently influence respiratory health, we 

might expect that with especially high levels 

of either exposure, exacerbations likely occur, 

regardless of the second exposure. Effectively, 

very high exposures may overpower any 

potential interaction effects.

Potential saturation effects call for careful 

attention to the exposure range observed in 

any study, relative to normal exposure levels, to inform whether interactions should 

be expected and how to interpret observed 

interactions. For example, our group reported 

that asthmatic children of families reporting 

higher fear of violence showed less symptom 

improvement with allergen-reducing indoor 

environmental interventions (Clougherty 

et al. 2006). Counter to initial hypotheses, 

this result suggested saturation effects in our 

very high-exposure public housing cohort. 

Either fear of violence or allergen exposures 

may have been high enough to independently 

induce or maintain symptoms.

The need for toxicologic research. Because of 

strong potential confounding between stressors 

and pollution, epidemiologic methods alone 

are unlikely to fully differentiate their effects 

or resolve spatial confounding. Additionally, 

chronic air pollution exposure may contribute to HPA-axis stimulation and stress processes (Sirivelu et al. 2006). Thus, experimental 

studies using well-developed animal models 

of social stress (e.g., monkeys, rats) are needed 

to delineate these effects. Toxicologic data can 

improve causal inference and interpretability 

by randomizing exposures, controlling their 

temporality and intensity, and, importantly, 

can help elucidate physiologic mechanisms for 

stress-pollution interactions.

Several authors have investigated stress as 

a modifier of neurologic effects of lead in animal models. Cory-Slechta et al. (2004) examined separate and combined effects of restraint 

stress and lead in pregnant dams on corticosterone, neurotransmitter levels, and behavioral 

learning. They found significant interactions, 

generally more prominent in female offspring, 

and noted that lead alone influenced corticosterone, suggesting that lead may influence later-life susceptibility (Virgolini et al. 

2005, 2006). They observed strongly altered 

HPA-axis function with both lead and stress, 

separately and in combination, providing a 

model for better understanding the etiology 

of conditions linked to both exposures and 

potentially mediated through HPA function, 

including obesity, hypertension, diabetes, 

anxiety, schizophrenia, and depression (RossiGeorge et al. 2009).

We recently compared short-term respiratory response to concentrated fine particulate air pollution (CAPs) among chronically 

stressed and unstressed rats. Using the social 

dominance paradigm, a rat model of social 

stress (Hotsenpiller and Williams 1996; 

Luciano and Lore 1975), we introduced male 

test rats individually into the cage of an older, 

larger male, over an 8-week period, to establish chronic stress conditions. Test animals 

were exposed to controlled CAPs for 5 hr on 

days after stress exposures. Across four exposure groups [stress/CAPs; stress/filtered air 

(FA); nonstress/CAPs; nonstress/FA], animals exposed to both stress and CAPs displayed elevated C-reactive protein and altered 

respiratory function relative to other groups, 

with higher frequencies and briefer pauses 

after inspiration and expiration, suggesting 

a shallower, more rapid breathing pattern 

(Clougherty et al. 2008).

Experimental studies involving humans. 

Experimental studies have identified physiologic parameters associated with stressors 

in humans (exam stress, public speaking). 

Although these studies can examine only shortterm, relatively benign stressors, they do allow 

for controlled, randomized stressor exposures

that are not feasible in the community setting. Fiedler et al. (2005) examined combined 

effects of stressors (public speaking, math challenge) and oxidation by-products of indoor 

volatile organic carbons and ozone, prevalent 

in office settings, on cortisol, respiratory function, and symptoms (anxiety, eye/nose irritation, respiratory symptoms) at multiple time 

points. They found that stress predicted anxiety symptoms and cortisol, outweighing any 

potential interaction with pollution (Fiedler 

et al. 2005). Such experimental studies cannot mimic the lifelong stress and pollution 

exposures associated with low SES but help to 

elucidate some mechanisms for stress-related 

susceptibility and, importantly, allow for the 

separation of persistently correlated exposures, 

otherwise difficult to delineate.

Pollution and pollution sources as psychosocial stressors. Health geographers influenced 

by the environmental justice movement have 

long understood that neighborhood pollution sources, including highways, power 

plants, and smokestacks, can send strong 

messages to residents about the value of their 

health and well-being to the larger society 

(Bullard 1990). Indeed, the study of air pollution effects on health has historically considered its psychological effects (Colligan 

1981; Strahilevitz et al. 1979), including 

psychosocial impacts of perceived exposure 

(Rotton et al. 1979) on vigilance (Horvath 

and Dahms 1971; Putz et al. 1977), test performance (Hore and Gibson 1968), irritation 

(Jones 1978), aggression (Rotton et al. 1979), 

behavior (Evans and Jacobs 1981), neurologic 

effects (Hore and Gibson 1968), and vision 

impairment (Lagerwerff 1963). More recent 

evidence indicates that air quality below 

regulatory guidelines can be detected by 
Stress and air pollution susceptibility

Environmental Health Perspectives • volume 117 | number 9 | September 2009 1355

residents, with negative health consequences 

(Forsberg et al. 1997), although perceived 

air quality can also be influenced by disease 

status (Piro et al. 2008). Indeed, it can be difficult to distinguish health effects produced 

by the physical aspects of air pollution from 

its psychosocial health effects in communities 

near toxic sites (Elliot et al. 1993; Eyles et al. 

1993), to separate both pollution-derived 

effects from those of other spatially correlated 

stressors, or to establish directionality. To 

better elucidate this complex synergy among 

exposure pathways, environmental exposure assessment and risk management may 

ultimately consider both tangible physical 

and psychosocial effects of pollution to fully 

understand the mechanisms linking air pollution, stress, and susceptibility.

Additional Questions

to be Explored

Many questions about stress-related pollution 

susceptibility remain. We raise several here, 

describing each only briefly, and hope these 

issues will be explored in detail in coming years.

To which pollutants and health outcomes is stress-related susceptibility relevant? 

A few studies demonstrate significant stressrelated modification in air pollution effects 

on respiratory health, particularly asthma 

onset (Clougherty et al. 2007) and exacerbation (Chen et al. 2008; Clougherty et al. 

2006). Stress may also modify relationships 

between bone lead and cardiovascular outcomes (e.g., hypertension) (Peters et al. 2007) 

and, in the same data set, heart rate variability (Clougherty JE, Peters JL, Schwartz J, 

Kubzansky L, unpublished data). A growing 

toxicology literature demonstrates stress-related susceptibilities to neurocognitive effects 

of lead and polychlorinated biphenyls, including neurologic damage and hippocampal function (Cory-Slechta et al. 2004). These vastly 

different exposures and outcomes demonstrating stress–pollutant interactions and the many 

physiologic systems affected by stress (e.g., 

sympathetic regulation, immune function, 

glucocorticoid production) suggest potential 

stress-related modifications in a wide range of 

pollutant exposures on health outcomes.

Are these interactions different in illness 

onset than in exacerbation? For preexisting 

illness, many factors may modify stress effects 

on illness severity and chronicity, including 

current medical treatment and comorbidities. The progression of preexisting illness, 

if influenced by stress, may also change the 

relevant temporalities, as later stress could 

plausibly modify recovery from environmentally derived illness. Thus, stress–pollution 

interactions may be even more complicated 

for existing illness, and careful attention to 

temporality and confounding (e.g., by medical treatment) is even more important. Some 

evidence suggests that stress may modify 

pollution effects in exacerbating preexisting 

asthma (Chen et al. 2008; Clougherty et al. 

2006), although both studies produced associations opposite to hypotheses (stronger pollution effects with lower stress). More generally, 

attention to distinguishing processes related to 

illness onset from illness progression or exacerbation will be critical in assessing whether 

interactions are robust or should be expected 

in healthy populations.

Are there critical periods for stress and 

pollution exposures across the life course? 

Different diseases are relevant at different 

life stages. Asthma is among the most prevalent chronic illnesses of childhood, whereas 

cardiovascular illness generally afflicts older 

persons. Because the life-course distribution 

of illness varies considerably, relationships 

among stress, susceptibility, and illness likely 

also vary with age. Although stress can be 

toxic at any age, there may be critical periods, 

such as during early immune development, 

when it is particularly influential in shaping 

future susceptibility and disease risk (Evans 

and English 2002).

Parental stress has been used to examine stress exposures in young children, and 

research supports inverse associations for both 

mother’s SES and depressive states on children’s stress hormone levels (Lupien et al. 

2000). Prospective studies have linked caregiver stress to infant wheeze (Wright et al. 

2002), and maternal stress during pregnancy 

may influence immune function and health 

in neonates (Weiss and Bellinger 2006). 

Maternal air pollution exposures associated 

with low birth weight (Gouveia et al. 2004) 

may increase later childhood respiratory disease risk. Stress exposures during development 

may produce broad biological and psychological vulnerabilities, affecting neuroendocrine, 

immune, metabolic, and growth processes 

(Viltart and Vanbesien-Maillot 2007).

Although not entirely immutable, these effects 

may have permanent and compounding consequences, especially if not addressed early 

(Cicchetti and Walker 2001; McEwen 2008).

What are the roles of gender/sex and race/

ethnicity in shaping stress-related susceptibility to pollution? It is beyond the scope of this 

review to describe the myriad societal-level 

sources of stress. However, ongoing research 

in this area will be informed by the growing 

literatures on racism as a prevalent stressor, 

and on sex and gender differences in psychological and physiologic responses to stress and 

susceptibility.

Racial and ethnic minority groups 

in the United States are often differentially 

exposed to psychosocial stressors and physical contaminants in their homes, neighborhoods, and workplaces (Bullard 1990). The 

environmental justice movement has drawn 

attention to disproportionate pollution exposures in minority and low-income communities (Krieger 1990), but only recently has

attention been directed to combined pollution exposures and greater susceptibility in 

these communities (Clougherty et al. 2007; 

Evans and English 2002; Morello-Frosch 

and Shenassa 2006; National Environmental 

Justice Advisory Council 2004). Experiences of 

racism as a stressor have been associated with 

negative physical and emotional health effects 

(Borrell et al. 2006; Clark et al. 1999; Krieger 

and Sidney 1996; Kwate et al. 2003; Landrine 

and Klonoff 1996; Thompson 1996) modified 

by coping practices and social support (Kwate 

et al. 2003). Experiences of racial discrimination predicted poorer birth outcomes among 

women with Arabic names in California after 

11 September 2001 (Lauderdale 2006). There 

is also evidence of poorer health, including 

mortality, for U.S. persons than for foreignborn persons of the same ethnicity, especially 

Hispanics (Singh and Hiatt 2006). Effects of 

race and racism are not fully mediated through 

social class (Kwate et al. 2003) and are not generally attributable to genetic variation (Krieger 

2005). Race-related stressors may contribute 

to “weathering” or physiologic wear and tear 

(Geronimus 1992; Goodman et al. 2005; 

Merritt et al. 2004). Hypertension onset, for 

example, may be four to seven times higher 

among low-SES than among high-SES AfricanAmerican men (James et al. 2006). African 

Americans also have higher rates of cardiovascular illness (Pappas et al. 1993) and low birth 

weight (David and Collins 1997) relative to 

Caucasians with comparable education.

Sex and gender differences in stress 

and susceptibility may be significant. The 

distinction between gender (socially influenced behaviors) and sex (biology, including hormonal composition, sex organs, and 

anthropometric measures) is comparable 

with that between exposure and susceptibility. Sex differences have been observed in 

air pollution–health associations. After early 

childhood, more studies report greater risks 

among women and girls (Luginaah et al. 

2005; Oftedal et al. 2008; Rojas-Martinez 

et al. 2007; Rosenlund et al. 2008), possibly explained, in part, by biological sex differences in lung capacity, hormonal status, 

inflammation, or airway particle deposition 

(Kim and Hu 1998; Kohlhaufl et al. 1999). 

Gendered social and behavioral patterns also 

matter. Sex stratification in the workforce and 

work-related exposures are well documented 

(Arbuckle 2006; Messing and Stellman 2006). 

Among children, play activities may influence ventilation rate, creating exposure differences between boys and girls (McConnell 

et al. 2002). Common pollution exposures 

metrics may be differently accurate by gender; residential exposures may better capture 
Clougherty and Kubzansky

1356 volume 117 | number 9 | September 2009 • Environmental Health Perspectives

exposures for stay-at-home parents (usually 

mothers) than for working adults (Dietrich 

et al. 2008; Jedrychowski and Krzyzanowski 

1989). Physiologic stress responses differ 

by sex (Sundaram et al. 2004; Taylor et al. 

2000), as does observed effect modification 

by SES (Wheeler and Ben-Shlomo 2005), 

such that gendered stress assessment may be 

needed to fully understand stress-linked effect 

modification for air pollution.

To what extent are the effects of SES 

attributable to stress? As described, there is 

growing evidence of SES effect modification in the air pollution–disease relationship.

ACS studies reported stronger health effects 

of air pollution among less-educated adults 

(Krewski et al. 2000), and time-series studies 

report the same (Jerrett et al. 2004; Kan et al. 

2008; Lin et al. 2004; Martins et al. 2004), 

although these air pollution studies have not 

identified causal components of SES shaping susceptibility. Like air pollution, SES is 

a complex exposure mix accumulated over 

the life course, potentially including poorerquality education; nutrition; housing; health 

care; health behaviors; pollution exposures in 

the home, community, and workplace; perceived social position; and other stressors. 

Indeed, newer variants of the allostatic load 

model incorporate primary (e.g., perceived 

stress, psychological response) and secondary 

(e.g., smoking, sleep, dietary behaviors) manifestations of stress (McEwen 2006). Growing 

evidence links low SES to perceived stress and 

distress (Adler et al. 1994; Miller and Chen 

2007) and to biological markers of stress-related susceptibility (Lupien et al. 2001). Some 

of these studies used allostatic load models to 

link SES to distress and markers of disease risk 

(e.g., metabolic dysregulation) (Kubzansky 

et al. 2000). Other studies link allostatic load 

parameters to morbidity and mortality, suggesting that allostatic load may mediate relationships between SES and mortality, after 

accounting for demographic characteristics 

and physician-diagnosed illness (Seeman et al. 

2004).

Among children, low SES may be a marker 

of early exposure to adversity. Recent studies 

link low childhood SES to epigenetic changes 

in messenger ribonucleic acid (mRNA) for the 

glucocorticoid receptor and toll-like receptor 4, indicative of proinflammatory profiles 

associated with asthma and allergic illness 

(Miller and Chen 2007). Low-SES children 

6–10 years of age have shown higher basal cortisol levels than higher-SES children (Lupien 

et al. 2001). Children of parents reporting 

higher stress display physiologic hyperresponsiveness, and low-income children of depressed 

mothers show sex-specific physiologic 

responses: elevated cortisol in girls, HPA-axis 

hypoactivity in boys (Fernald et al. 2008). 

Children of depressed mothers can display 

altered adrenocorticotropic hormone and 

corticotropin-releasing hormone production 

into young adulthood (Ronsaville et al. 2006). 

Evidence suggesting that stress is a key mediator for SES effects on health is not universally 

endorsed, and associations between SES and 

stress-related biological changes are not always 

positive (Dowd and Goldman 2006). Authors 

have argued that psychosocial factors are inextricably bound to material factors in developed 

countries; therefore, the accumulated evidence 

does not unequivocally demonstrate an independent pathway by which psychosocial stress 

may link SES to physical health (Macleod and 

Davey Smith 2003). Other aspects of SES 

(e.g., nutrition, health care) may also influence pollution susceptibility, and methods are 

needed to determine their effects. We believe 

that the evidence to date is broadly suggestive 

of a link between SES and physiologic susceptibility, a significant portion of which may be 

explained by life stress. Continued research in 

this area is valuable, especially as it improves 

our understanding of the pathways through 

which physical exposures, including pollution, may differently impinge on the health of 

vulnerable populations.

Conclusions

There is tremendous potential, although much 

work still to be done, in understanding combined effects of social and physical environmental exposures. These topics are exceedingly 

complicated. Accurately characterizing both 

social and physical exposures is a significant 

challenge that must be performed carefully, 

especially in light of potential confounding 

across the exposures of interest, before analyzing and interpreting interactions.

The issues we have highlighted here—

temporal relationships between stressors and 

pollution; nonlinearity and saturation effects; 

spatial colinearity across exposures; age-related 

susceptibility and critical periods; and distinctions between processes related to illness 

etiology and exacerbation—will be critical in 

exploring social–environmental interactions. 

These factors are significant enough to distort 

observed associations (e.g., saturation effects 

may reverse interactions at high exposures; 

treatment can mask exacerbations of pre-existing illness). With sustained attention to these 

issues, we can work toward a clearer, richer 

understanding of complex effects among 

social and physical environmental exposures 

on health.

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